This invention relates to novel compositions of matter containing optically pure (+) doxazosin. These compositions possess potent long lasting anti-hypertensive activity while avoiding adverse effects associated with the administration of the racemic mixture of doxazosin including but not limited to orthostatic hypotension, nausea, lethargy, fatigue and dizziness. Also disclosed are methods for treating hypertension in a human while avoiding adverse effects that are associated with the racemic mixture of doxazosin by administering the (+) isomer of doxazosin to said human.
The active compound of these compositions and methods is an optical isomer of doxazosin, which is described by Young and Brogden in Drugs, 35, 525-541 (1988) and U.S. Pat. No. 4,188,390. Chemically, the active compound is the (+) isomer of 4-amino-2- 4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl!-6,7-dimethoxyquin azoline also known as 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4- (2,3-dihydro1,4-benzodioxan-2- yl)carbonyl!piperazine hereinafter referred to as doxazosin.
(+) Doxazosin, which is the subject of the present invention, is available commercially only as the 1:1 racemic mixture. That is, (+) doxazosin is available only as a mixture of optical isomers, called enantiomers. The racemic mixture of doxazosin is commercially available for administration as a methanesulfonate (mesylate) salt, but extensive pharmacology has been published on the hydrochloride salt as well.
Many organic compounds exist in optically active forms, i.e. they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. There is no correlation between nomenclature for the absolute stereochemistry and for the rotation of an enantiomer. Thus, D-lactic acid is the same as (-) lactic acid, and L-lactic acid is (+). For a given chemical structure, these compounds, called stereoisomers, are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric or racemic mixture.
Doxazosin is a representative of a group of drugs that block .alpha..sub.1 adrenoceptors. .alpha..sub.1 Receptors are innervated by postganglionic sympathetic neuronal fibers and are located in many body systems, including the cardiovascular system, where they are found primarily on smooth muscle cells in arterioles and venous capacitance vessels. Activation of these receptors by the physiological neurotransmitter substance, norepinephrine, increases peripheral arteriolar resistance and decreases venous capacitance. Specific .alpha..sub.1 antagonists act to lower blood pressure and this is their primary current clinical indication.
Historically, .alpha..sub.1 antagonists such as phenoxybenzamine and phentolamine were not particularly useful as antihypertensive agents largely because of the substantial tachycardia which accompanied their use. The tachycardic effect was however due primarily to the concomitant presynaptic .alpha..sub.2 receptor blocking activity of the early .alpha. antagonists. Inhibition of .alpha..sub.2 receptors acts presynaptically to augment the release of norepinephrine from adrenergic neurons. This stimulated the post-junctional sympathetic adrenoceptors in the heart which are predominately of the .beta. adrenergic type. New, more specific, .alpha..sub.1 receptor antagonists produce much less tachycardia than the older compounds. During long term therapy the vasodilation persists with the newer .alpha..sub.1 antagonists, but the remaining tachycardia, renin release and increased cardiac output, which are all reflex mediated, return to normal. In addition, there may be a component to .alpha..sub.1 receptor inhibition that contributes to the amelioration of the reflex mediated mechanisms.
A troublesome cardiovascular problem related to the use of .alpha..sub.1 receptor antagonists is orthostatic hypotension. Symptomatic orthostatic hypotension is most likely to occur with high initial doses of .alpha..sub.1 antagonists or may occur when the dose is increased rapidly. A modest degree of fluid retention which is another result of vasodilation may also be observed when .alpha..sub.1 antagonists are used as single agents.
Doxazosin is a selective .alpha..sub.1 adrenergic receptor blocking agent structurally related to prazosin. Its oral bioavailability is good and the plasma half life in man is approximately 10 hours following both oral and intravenous administration.
Doxazosin has a single chiral center located on the carbon adjacent to the carboxyl group. This gives rise to a pair of enantiomers which have been resolved by Ley et al. Recent Advances in Chiral Separations, Steven and Wilson Editors, Plenum Press, New York (1991) pages 97-103! on an analytical scale (0.52 .mu.g), but there are no reports in the literature of a preparative-scale separation of the enantiomers.
The racemic mixture of doxazosin is presently used primarily as an antihypertensive agent. In addition, there is a report that the administration of doxazosin leads to modestly decreased total cholesterol and LDL levels.
Many of the .alpha..sub.1 antagonists cause somewhat similar adverse effects. The incidence of reported side effects associated with racemic doxazosin-treated patients has varied among studies. The incidence of total side effects associated with doxazosin in patients treated for hypertension has ranged between 0 and 75%, but has generally been similar to that seen with other anti-hypertensive agents at dosages producing a similar reduction in blood pressure. The most frequently reported side effects have been postural hypotension, nausea, lethargy, fatigue and dizziness.
Thus it would be particularly desirable to find a compound with the advantages of the racemic mixture of doxazosin which would not have the aforementioned disadvantages.